ATBECHDEDKESFRGBGRITLI..NLSE......................RDIM360 - Ver 2.5 (21 Aug 1997) 2100000/1 2100000/20486782EUROPEAN PATENT SPECIFICATIONB119950809EP91115349.2199109111992092919940405enenen61360119901113US199508091995321992052719922219950809199532199411046 6C 07C 255/42 A 6C 07D 261/08 B 6C 07D 413/04 BdeVerfahren zur Herstellung von alpha-((Dialkylamino)substituiertes-methylen)-beta-oxo-(substituiertes)-propannitrileenImproved process for the synthesis of alpha-((dialkylamino)substituted-methylene)-beta-oxo-(substituted) propanenitrilesfrProcédé de préparation d'alpha-(méthylène-(substitués de dialkylamino))-bêta-oxo-(substitués)-propanenitrilesEP-A- 0 129 846EP-A- 0 168 737EP-A- 0 176 846US-A- 4 197 310CHEMICAL ABSTRACTS, vol. 87, no. 9, 29 August 1977, Columbus, Ohio,US; abstract no. 68055Y, N.LATIF ET AL: 'Reaction of tetrabomo-o-benzoquinone...' page 520 ;column 1 ;CHEMICAL ABSTRACTS, vol. 75, no. 3, 19 July 1971, Columbus, Ohio,US; abstract no. 20354V, H. SAIKACHI ET AL: 'Synthesis of furan derivatives...'page 459 ;column 2 ;Dusza, John P.24 Convent RoadNanuet, New York 10954USChurch, Robert F.8 Fado LaneCos Cob, Connecticut 06807USAMERICAN CYANAMID COMPANY00212594CYANAMID COMPANY, AMERICANOne Cyanamid PlazaWayne, NJ 07470-8426USWächtershäuser, Günter, Prof. Dr.00012711Patentanwalt, Tal 2980331 MünchenDEATBECHDEDKESFRGBGRITLINLSE19920527199222 BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION

The invention relates to a process for the synthesis of α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds and to novel substituted isoxazole compounds useful as intermediates in the process.

2. DESCRIPTION OF THE PRIOR ART

The α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds are important intermediates for the preparation of therapeutic aryl and heteroaryl [7-(aryl and heteroaryl)pyrazolo(1,5-a)-pyrimidin-3-yl]methanone compounds which are useful as anxiolylic, antiepileptic, sedative-hypnotic and skeletal muscle relaxant agents. The aryl and heteroaryl [7-(aryl and hetroaryl)-pyrazolo [1,5-a] pyrimidin-3-yl]methanone compounds and uses for such compounds are described in U.S. 4,521,422.

In U.S. 4,900,836, a series of reactions in which the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds are utilized to produce the [7-(alkyl and hetroaryl)pyrazolo (1,5-a)-pyrimidin-3-yl]methanone compounds is described. This reference also describes the synthesis of the α-[(dialkylamino) substituted methylene]-β-oxo-(substituted) propanenitrile compounds via the reaction of a substituted acetonitrile with a dimethylformamide dimethylacetal.

It has now been found that α-[(dialkylamino) substituted methylene]β-oxo-(substituted) propane nitrile compounds may be advantageously synthesized via reaction of a substituted isoxazole with a dialkylamide dimethylacetal. The use of substituted isoxazole compounds in the production of α-[(dialkylamino)substituted methylene]-β-oxo(substituted)propanenitrile compounds has not been taught nor suggested by the art.

Certain substituted isoxazole compounds and their synthesis are known. For example, 5-(2,3,4,5-tetra-fluorophenyl)-isoxazole (Chem. Abst. Registry No. 110985-65-4), 5-(2,4-dichloro-5-fluorophenyl) isoxazole (Registry No. 103318-74-6), 5-(2,3,-dichloro-phenyl) isoxazole (Registry No. 76344-98-4), 5-(5-nitro-2-furyl)-isoxazole (Registry No. 32332-91-5), 5-(4-methylphenyl)-isoxazole (Registry No. 7064-35-9), 5-(m-chloro phenyl) isoxazole (Registry No. 7064-34-8), 5-(m-bromo phenyl) isoxazole (Registry No. 7064-33-7), 5-(p-chloro-phenyl) isoxazole (Registry No. 7064-32-6), 5-(p-bromo phenyl) isoxazole (Registry No. 7064-31-5), N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-2-5-isoxazolyl)-3-thiophenesulfonamide (Registry No. 103118-33-8), 3-hydroxy-4-(5-isoxazolyl)-2(5H)-foranone (Registry No. 84-608-81-1) and 5-phenyl isoxazole (Registry No. 1006-67-3) are known. Other substituted isoxazole compounds including those claimed herein are not known.

SUMMARY OF THE INVENTION

The invention provides an improved process for the large scale production of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds which may be represented by the following structural formula:
wherein R is lower alkyl(C₁-C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁-C₃) and alkoxy(C₁-C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁-C₃), methylenedioxy, alkylthio(C₁-C₃), alkylsulfonyl(C₁-C₃), amino, alkanoyl(C₁-C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁-C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁-C₃), naphthalenyl, pyrazinyl, and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁-C₃). The improved process comprises reacting an R₁ substituted isoxazole having the formula
wherein R₁ is as defined above with a dialkylamide dimethylacetal having the formula
wherein R and R² are as defined above at a temperature from 50°C to 100°C and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The invention also provides certain novel R₁ substituted isoxazole compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The process and compounds of the present invention are described in the following reaction scheme I:
   In accordance with the above reaction scheme a 1-(cyclicsubstituted)ethanone (1), where R₁ is as described above, is reacted with dimethylformamide dimethyl acetal (2) for 15 hours at 50°-100°C. Evaporation and recrystallization gives the 3-dimethylamino-1-(substituted)-2-propen-1-one (3).

The 3-dimethylamino-1-(substituted)-2-propen-1-one compounds (3) and their synthesis are described in greater detail in U.S. 4,178,449 (col 2 lines 44-54), U.S. 4,281,000 (col 2 lines 28-34), and U.S. 4,236,005 (col 2 lines 45-54). Related compounds are also known from EP-A-0 176 846 and EP-A-0 129 846.

The 3-dimethylamino-1-(substituted)-2-propen-1-one (3) is reacted with hydroxylamine hydrochloride in absolute methanol for 2 hours at a temperature from 50° to 100°C. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. Concentration of the eluate gives the desired substituted isoxazole (5) which is reacted with a dialkylamide dimethylacetal (6) at a temperature from 50° to 100°C for 4 hours. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. On cooling and/or concentrating the methylene chloride solution, the desired α-[(dialkylamino)substituted methylene]-β-oxo-(substituted) propanenitrile (7) crystallizes.

The formation of an oxazole with hydroxylamine hydrochloride departing from a chlorovinyl phenyl ketone is known from EP-A-0 168 737.

As described in U.S. 4,900,836, the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitriles find utility as intermediates in the preparation of therapeutic aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a)pyrimidin-3-yl] methanones. As described in U.S. 4,521,422 the aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a) pyrimidin-3-yl]methanones are useful as anxiolylic, antiepileptic, sedative-hypnotic, and skeletal muscle relaxant agents.

The above described process is an improvement over the procedure described in U.S. Pat. No. 4,900,836. The 1-(cyclicsubstituted)ethanones are readily available and inexpensive; the over all yields are higher; and the reaction work-ups are less labor and time intensive.

The following non-limiting examples illustrate the process of the present invention as well as the preparation of the novel compounds isoxazole intermediates.

Example 1 3-Dimethylamino-1-(3-thienyl)-2-propen-1-one

A mixture of 48.4 g of 3-acetylthiophene and 75 ml of dimethylformamide dimethyl acetal, under nitrogen, is heated for 15 hours on a steam bath. The reaction is concentrated in vacuo and the residue crystallized from methylene chloride/hexane to give 60.55 g (87%) of the desired product, mp 89-90°C.

Using the general procedure of Example 1, the following compounds of Example 2-26 shown in Table 1 are prepared.

Example 27

A mixture of 58.1 g of (3-dimethylamino-1-(3-thienyl)-2-propen-1-one, 23.4 g of hydroxylamine hydrochloride and 250 ml of commercial absolute methanol is heated on a steam bath for 2 hours. The reaction is concentrated in vacuo, partitioned between methylene chloride and water and the organic layer dried over sodium sulfate. The methylene chloride is passed thru a short column of hydrous magnesium silicate and concentrated in vacuo to give 41.25 g (85%) of the desired product as a red-orange oil which solidified on standing. CI-MS: M/z 151(M⁺).

Using the general procedure of Example 27, the following compounds of Example 28-52, shown in Table II are prepared.

Example 53 α-[(Dimethylamino)methylene]-β-oxo-3-thiophenepropanenitrile

A mixture of 41.2 g of 5-(3-thienyl)isoxazole and 36.0 g of dimethylformamide dimethylacetal, under nitrogen, is heated on a steam bath for 4 hours. The reaction is concentrated in vacuo to give a viscous oil which solidified. The residue is dissolved in methylene chloride and passed thru a short column of hydrous magnesium silicate. On cooling, 31.76 g of the desired product is obtained, mp 118-119°, CI-MS:m/z 206(M⁺). Concentrating in vacuo the methylene chloride gives an additional 20.2 g of product. (Total recovered 51.96 g, 92%).

Using the general procedure of Example 53, the following compounds of Example 54-78, shown in Table III are prepared.

A process for producing compounds of the formula: wherein R is lower alkyl(C₁-C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁-C₃) and alkoxy(C₁-C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁-C₃), methylenedioxy, alkylthio(C₁-C₃), alkylsulfonyl(C₁-C₃), amino, alkanoyl(C₁-C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁-C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁-C₃), naphthalenyl, pyrazinyl and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁-C₃); which comprises: reacting a substituted isoxazole having the formula with dialkylamide dimethylacetal having the formula at a temperature from 50 to 100°C and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The process of Claim 1, wherein said substituted isoxazole is prepared by reacting a 3-dimethylamino-1-substituted-2-propen-1-one having the formula with hydroxylamine hydrochloride in absolute methanol at a temperature from 50°C to 100°C. The process of Claim 2 wherein said 3-dimethylamino-1-substituted 2-propen-1-one is prepared by reacting a 1-(cyclic substituted) ethanone having the formula with dimethylformamide dimethylacetal at a temperature of from 50°C to 100°C. The process of Claim 1, wherein α-[(dimethyl-amino)methylene]-β-oxo-3-thiophenepropanenitrile, 5-bromo-α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile, α-[(dimethylamino)methylene]-5-methyl-β-oxo-2-furanpro-panenitrile, α-[(dimethylamino)methylene]-3-ethyl-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-4-nitro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-β-oxo-tricyclo[3.3.1.13,7]decane-1-propanenitrile, α-[(dimethylamino)methylene]-β-oxo-4-biphenylpropanenitrile, 3,4-dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-3, 4-dimethyl-β-oxo-benzenepropanenitrile, 2, 4dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-2,6-difluoro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene] -4-methyl-β-oxo-2-thiophene-propanenitrile, α-[(dimethylamino)methylene]-1-methyl-β-oxo-1H-pyrrole-2 -propanenitrile,α-[(dimethylamino)methylene]-3-methyl-β-oxo-2-thiophene-propanenitrile,α-[(dimethylamino) methylene]-2,4-difluoro-β-oxo-benzenepropanenitrile or α-[(di-methylamino)methylene]-2,5-difluoro-β-oxo-benzenepropanenitrile is produced. A compound having the formula wherein R₁ is selected from the group consisting of 3-thienyl, 2-furanyl, 2-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2-thienyl, 2,4 difluorophenyl, 2,5 difluorophenyl. A process for producing compounds of the formula: wherein R is lower alkyl(C₁-C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁-C₃) and alkoxy(C₁-C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁-C₃), methylenedioxy, alkylthio(C₁-C₃), alkylsulfonyl(C₁-C₃), amino, alkanoyl(C₁-C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁-C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁-C₃), naphthalenyl, pyrazinyl and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁-C₃); which comprises: reacting a substituted isoxazole having the formula with dialkylamide dimethylacetal having the formula at a temperature from 50 to 100°C and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The process of Claim 1, wherein said substituted isoxazole is prepared by reacting a 3-dimethylamino-1-substituted-2-propen-1-one having the formula with hydroxylamine hydrochloride in absolute methanol at a temperature from 50°C to 100°C. The process of Claim 2 wherein said 3-dimethylamino-1-substituted 2-propen-1-one is prepared by reacting a 1-(cyclic substituted) ethanone having the formula with dimethylformamide dimethylacetal at a temperature of from 50°C to 100°C. The process of Claim 1, wherein α-[(dimethyl-amino)methylene]-β-oxo-3-thiophenepropanenitrile, 5-bromo-α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile, α-[(dimethylamino)methylene]-5-methyl-β-oxo-2-furanpro-panenitrile, α-[(dimethylamino)methylene]-3-ethyl-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-4-nitro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-β-oxo-tricyclo[3.3.1.13,7]decane-1-propanenitrile, α-[(dimethylamino)methylene]-β-oxo-4-biphenylpropanenitrile, 3,4-dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-3, 4-dimethyl-β-oxo-benzenepropanenitrile, 2, 4dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-2,6-difluoro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene] -4-methyl-β-oxo-2-thiophene-propanenitrile, α-[(dimethylamino)methylene]-1-methyl-β-oxo-1H-pyrrole-2 -propanenitrile,α-[(dimethylamino)methylene]-3-methyl-β-oxo-2-thiophene-propanenitrile,α-[(dimethylamino) methylene]-2,4-difluoro-β-oxo-benzenepropanenitrile or α-[(di-methylamino)methylene]-2,5-difluoro-β-oxo-benzenepropanenitrile is produced. Verfahren zum Herstellen von Verbindungen der Formel worin R Niederalkyl(C₁-C₃) ist; R₁ ausgewählt ist aus der Gruppe bestehend aus Phenyl, Phenyl, das mit einem Mitglied aus der Gruppe substituiert ist, ausgewählt aus Halogen, Nitro, Alkyl(C₁-C₃) und Alkoxy(C₁-C₃); Phenyl, das di- oder tri-substituiert ist durch Methoxy, Halogen und Niederalkyl; Phenyl, das durch ein Mitglied aus der Gruppe substituiert ist, bestehend aus Dialkylamino(C₁-C₃), Methylendioxy, Alkylthio(C₁-C₃), Alkylsulfonyl(C₁-C₃), Amino, Alkanoyl(C₁-C₃)amino, Trifluormethyl und Phenyl; Thienyl; Thienyl, das durch eines oder zwei Mitglieder aus der Gruppe substituiert ist, ausgewählt aus Halogen und Alkyl(C₁-C₃); Furanyl; Furanyl, das durch ein oder zwei Mitglieder aus der Gruppe substituiert ist, ausgewählt aus Alkyl(C₁-C₃), Naphthyl, Pyrazinyl und Pyrrolyl; und R₂ ist ausgewählt aus der Gruppe bestehend aus Wasserstoff und Niederalkyl(C₁-C₃), umfassend das Umsetzen eines substituierten Isoxazols der Formel mit einem Dialkylamid-dimethylacetal der Formel bei einer Temperatur von 50°C bis 100°C und Gewinnen des so hergestellten α-[(Dialkylamino)substituierten Methylen]-β-oxo-(substituierten)-propannitrils. Verfahren nach Anspruch 1, worin das substituierte Isoxazol hergestellt wird durch Umsetzen eines 3-Dimethylamino-1-substituierten-2-propen-1-on der Formel mit Hydroxylamin-Hydrochlorid in absolutem Methanol bei einer Temperatur von 50°C bis 100°C. Verfahren nach Anspruch 2, worin das 3-Dimethylamino-1-substituierte-2-propen-1-on hergestellt wird durch Umsetzen eines 1-(cyclisch-substituierten)Ethanons der Formel mit Dimethylformamid-dimethylacetal bei einer Temperatur von 50°C bis 100°C. Verfahren nach Anspruch 1, worin α-[(Dimethylamino)methylen]-β-oxo-3-thiophenpropannitril, 5-Brom-α-[(dimethylamino)methylen]-β-oxo-2-thiophenpropannitril, α-[(Dimethylamino)methylen]-5-methyl-β-oxo-2-furanpropannitril, α-[(Dimethylamino)methylen]-3-ethyl-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-4-nitro-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-β-oxo-tricyclo[3.3.1.13,7]decan-1-propannitril, α-[(Dimethylamino)methylen]-β-oxo-4-biphenylpropannitril, 3,4-Dichlor-α-[(dimethylamino)methylen]-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-3,4-dimethyl-β-oxo-benzolpropannitril, 2,4-Dichlor-α-[(dimethylamino)methylen]-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-2,6-difluor-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-4-methyl-β-oxo-2-thiophenpropannitril, α-[(Dimethylamino)methylen]-1-methyl-β-oxo-1H-pyrrol-2-propannitril, α-[(Dimethylamino)methylen]-3-methyl-β-oxo-2-thiophenpropannitril, α-[(Dimethylamino)methylen]-2,4-difluor-β-oxo-benzolpropannitril oder α-[(Dimethylamino)methylen]-2,5-difluor-β-oxo-benzolpropannitril hergestellt wird. Verbindung der Formel worin R₁ ausgewählt ist aus der Gruppe bestehend aus 3-Thienyl, 2-Furanyl, 2-Fluorphenyl, 4-Fluorphenyl, 2,6-Difluorphenyl, 2-Thienyl, 2,4-Difluorphenyl, 2,5-Difluorphenyl. Verfahren zum Herstellen von Verbindungen der Formel worin R Niederalkyl(C₁-C₃) ist; R₁ ausgewählt ist aus der Gruppe bestehend aus Phenyl, Phenyl, das mit einem Mitglied aus der Gruppe substituiert ist, ausgewählt aus Halogen, Nitro, Alkyl(C₁-C₃) und Alkoxy(C₁-C₃); Phenyl, das di- oder tri-substituiert ist durch Methoxy, Halogen und Niederalkyl; Phenyl, das durch ein Mitglied aus der Gruppe substituiert ist, bestehend aus Dialkylamino(C₁-C₃), Methylendioxy, Alkylthio(C₁-C₃), Alkylsulfonyl(C₁-C₃), Amino, Alkanoyl(C₁-C₃)amino, Trifluormethyl und Phenyl; Thienyl; Thienyl, das durch eines oder zwei Mitglieder aus der Gruppe substituiert ist, ausgewählt aus Halogen und Alkyl(C₁-C₃); Furanyl; Furanyl, das durch ein oder zwei Mitglieder aus der Gruppe substituiert ist, ausgewählt aus Alkyl(C₁-C₃), Naphthyl, Pyrazinyl und Pyrrolyl; und R₂ ist ausgewählt aus der Gruppe bestehend aus Wasserstoff und Niederalkyl(C₁-C₃), umfassend das Umsetzen eines substituierten Isoxazols der Formel mit einem Dialkylamid-dimethylacetal der Formel bei einer Temperatur von 50°C bis 100°C und Gewinnen des so hergestellten α-[(Dialkylamino)substituierten Methylen]-β-oxo-(substituierten)-propannitrils. Verfahren nach Anspruch 1, worin das substituierte Isoxazol hergestellt wird durch Umsetzen eines 3-Dimethylamino-1-substituierten-2-propen-1-on der Formel mit Hydroxylamin-Hydrochlorid in absolutem Methanol bei einer Temperatur von 50°C bis 100°C. Verfahren nach Anspruch 2, worin das 3-Dimethylamino-1-substituierte-2-propen-1-on hergestellt wird durch Umsetzen eines 1-(cyclisch-substituierten)Ethanons der Formel mit Dimethylformamid-dimethylacetal bei einer Temperatur von 50°C bis 100°C. Verfahren nach Anspruch 1, worin α-[(Dimethylamino)methylen]-β-oxo-3-thiophenpropannitril, 5-Brom-α-[(dimethylamino)methylen]-β-oxo-2-thiophenpropannitril, α-[(Dimethylamino)methylen]-5-methyl-β-oxo-2-furanpropannitril, α-[(Dimethylamino)methylen]-3-ethyl-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-4-nitro-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-β-oxo-tricyclo[3.3.1.13,7]decan-1-propannitril, α-[(Dimethylamino)methylen]-β-oxo-4-biphenylpropannitril, 3,4-Dichlor-α-[(dimethylamino)methylen]-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-3,4-dimethyl-β-oxo-benzolpropannitril, 2,4-Dichlor-α-[(dimethylamino)methylen]-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-2,6-difluor-β-oxo-benzolpropannitril, α-[(Dimethylamino)methylen]-4-methyl-β-oxo-2-thiophenpropannitril, α-[(Dimethylamino)methylen]-1-methyl-β-oxo-1H-pyrrol-2-propannitril, α-[(Dimethylamino)methylen]-3-methyl-β-oxo-2-thiophenpropannitril, α-[(Dimethylamino)methylen]-2,4-difluor-β-oxo-benzolpropannitril oder α-[(Dimethylamino)methylen]-2,5-difluor-β-oxo-benzolpropannitril hergestellt wird. Procédé de production des composés de formule :    dans laquelle :
   R représente un alkyle inférieur en C₁-C₃ ; R₁ est choisi dans le groupe constitué par phényle ; phényle substitué par un substituant choisi parmi les halogéno, nitro, alkyle en C₁-C₃ et alcoxy en C₁-C₃ ; phényle di- ou tri-substitué par méthoxy, halogéno et alkyle inférieur ; phényle substitué par un substituant du groupe constitué par di(alkyl en C₁-C₃)amino, méthylènedioxy, (alkyl en C₁-C₃)thio, (alkyl en C₁-C₃)sulfonyle, amino, (alcanoyl en C₁-C₃)amino, trifluorométhyle et phényle ; thiényle ; thiényle substitué par un ou deux substituants choisis parmi les halogéno et alkyle en C₁-C₃ ; furannyle ; furannyle substitué par un ou deux substituants choisis parmi les alkyle en C₁-C₃ ; naphtyle ; pyrazinyle, et pyrrolyle ; et R₂ est choisi dans le groupe constitué par l'hydrogène et les groupements alkyle inférieur en C₁-C₃ ; qui comprend : la réaction d'un isoxazole substitué de formule avec un diméthylacétal de dialkylamide de formule à une température allant de 50°C à 100°C et la récupération de l'α-[(dialkylamino)-(méthylène substitué)]-β-oxo-(propane substitué)-nitrile ainsi produit. Procédé selon la revendication 1, dans lequel ledit isoxazole substitué est préparé par réaction d'une 3-diméthylamino-2-propène-1-one substituée en 1 de formule avec du chlorhydrate d'hydroxylamine dans du méthanol absolu à une température allant de 50°C à 100°C. Procédé selon la revendication 2, dans lequel ladite 3-diméthylamino-2-propène-1-one substituée en 1 est préparée par la réaction d'une éthanone portant un substituant cyclique en 1, de formule avec du diméthylacétal de diméthylformamide à une température allant de 50°C à 100°C. Procédé selon la revendication 1, dans lequel on produit l'α-[(diméthylamino)méthylène)]-β-oxo-3-thiophènepropanenitrile, le 5-bromo-α-[(diméthylamino)méthylène)]-β-oxo-2-thiophènepropanenitrile, l'α-[(diméthylamino)méthylène]-5-méthyl-β-oxo-2-furannepropanenitrile, l'α-[(diméthylamino)méthylène]-3-éthyl-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène]-4-nitro-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène)]-β-oxo-tricyclo[3,3,1,13,7]-décane-1-propanenitrile, l'α-[(diméthylamino)méthylène]-β-oxo-4-biphénylepropanenitrile, le 3,4-dichloro-α-[(diméthylamino)méthylène]-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène]-3,4-diméthyl-β-oxo-benzènepropanenitrile, le 2,4-dichloro-α-[(diméthylamino)méthylène]-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène]-2,6-difluoro-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène)]-4-méthyl-β-oxo-2-thiophènepropanenitrile, l'α-[(diméthylamino)méthylène]-1-méthyl-β-oxo-1H-pyrrole-2-propanenitrile, l'α-[(diméthylamino)méthylène]-3-méthyl-β-oxo-2-thiophènepropanenitrile, l'α-[(diméthylamino)méthylène]-2,4-difluoro-β-oxo-benzènepropanenitrile ou l'α-[(diméthylamino)méthylène]-2,5-difluoro-β-oxo-benzènepropanenitrile. Composé de formule dans laquelle R₁ est choisi dans le groupe constitué par 3-thiényle, 2-furannyle, 2-fluorophényle, 4-fluorophényle, 2,6-difluorophényle, 2-thiényle, 2,4-difluorophényle, 2,5-difluorophényle. Procédé de production des composés de formule :    dans laquelle :
   R représente un alkyle inférieur en C₁-C₃ ; R₁ est choisi dans le groupe constitué par phényle ; phényle substitué par un substituant choisi parmi les halogéno, nitro, alkyle en C₁-C₃ et alcoxy en C₁-C₃ ; phényle di- ou tri-substitué par méthoxy, halogéno et alkyle inférieur ; phényle substitué par un substituant du coupe constitué par di(alkyl en C₁-C₃)amino, méthylènedioxy, (alkyl en C₁-C₃)thio, (alkyl en C₁-C₃)sulfonyle, amino, (alcanoyl en C₁-C₃)amino, trifluorométhyle et phényle ; thiényle ; thiényle substitué par un ou deux substituants choisis parmi les halogéno et alkyle en C₁-C₃ ; furannyle ; furannyle substitué par un ou deux substituants choisis parmi les alkyle en C₁-C₃ ; naphtyle ; pyrazinyle, et pyrrolyle ; et R₂ est choisi dans le groupe constitué par l'hydrogène et les groupements alkyle inférieur en C₁-C₃ ; qui comprend : la réaction d'un isoxazole substitué de formule avec un diméthylacétal de dialkylamide de formule à une température allant de 50°C à 100°C et la récupération de l'α-[(dialkylamino)-(méthylène substitué)]-β-oxo-(propane substitué)-nitrile ainsi produit. Procédé selon la revendication 1, dans lequel ledit isoxazole substitué est préparé par réaction d'une 3-diméthylamino-2-propène-1-one substituée en 1 de formule avec du chlorhydrate d'hydroxylamine dans du méthanol absolu à une température allant de 50°C à 100°C. Procédé selon la revendication 2, dans lequel ladite 3-diméthylamino-2-propène-1-one substituée en 1 est préparée par la réaction d'une éthanone portant un substituant cyclique en 1, de formule avec du diméthylacétal de diméthylformamide à une température allant de 50°C à 100°C. Procédé selon la revendication 1, dans lequel on produit l'α-[(diméthylamino)méthylène)]-β-oxo-3-thiophènepropanenitrile, le 5-bromo-α-[(diméthylamino)méthylène)]-β-oxo-2-thiophènepropanenitrile, l'α-[(diméthylamino)méthylène]-5-méthyl-β-oxo-2-furannepropanenitrile, l'α-[(diméthylamino)méthylène]-3-éthyl-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène]-4-nitro-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène)]-β-oxo-tricyclo[3,3,1,13,7]-décane-1-propanenitrile, l'α-[(diméthylamino)méthylène]-β-oxo-4-biphénylepropanenitrile, le 3,4-dichloro-α-[(diméthylamino)méthylène]-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène]-3,4-diméthyl-β-oxo-benzènepropanenitrile, le 2,4-dichloro-α-[(diméthylamino)méthylène]-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène]-2,6-difluoro-β-oxo-benzènepropanenitrile, l'α-[(diméthylamino)méthylène)]-4-méthyl-β-oxo-2-thiophènepropanenitrile, l'α-[(diméthylamino)méthylène]-1-méthyl-β-oxo-1H-pyrrole-2-propanenitrile, l'α-[(diméthylamino)méthylène]-3-méthyl-β-oxo-2-thiophènepropanenitrile, l'α-[(diméthylamino)méthylène]-2,4-difluoro-β-oxo-benzènepropanenitrile ou l'α-[(diméthylamino)méthylène]-2,5-difluoro-β-oxo-benzènepropanenitrile.